Evaluation of the potential therapeutic effects of a double-stranded RNA mimic complexed with polycations in an experimental mouse model of endometriosis

Abstract

Objective: To assess the therapeutic potential of polyinosine-polycytidylic acid, a double-stranded RNA molecule with selective proapoptotic and antiangiogenic activity, complexed with polyethyleneimine (pIC(PEI)) in treating endometriosis.

Design: A heterologous mouse model of endometriosis was created by injecting human endometrial fragments into the peritoneum. Endometrial fragments were engineered to express the fluorescent protein mCherry as a reporter to monitor status over the course of the 4-week study.

Setting: University-affiliated infertility center.

Animal(s): Ovariectomized and hormone-replaced nude mice (n = 30) injected with fluorescent-labeled human endometrial fragments at 4-6 weeks of age.

Intervention(s): Animals (n = 10 per group) were injected with vehicle (control), the anti-VEGF compound CBO-P11 (0.6 mg/kg), or pIC(PEI) (0.6 mg/kg) twice weekly over the course of 4 weeks.

Main outcome measure(s): Variations in the size of endometriotic implants were estimated by quantifying the expression of mCherry throughout the course of the experiment. Neovascularization, cellular proliferation, and apoptosis were estimated by quantitative immunofluorescence detection of PECAM, α-SMA, Ki67, and TUNEL.

Result(s): pIC(PEI) promoted a significant increase in apoptosis and a decrease in neovascularization in human fragments, but did not reduce the size of endometriotic implants.

Conclusion(s): While pIC(PEI) treatment had significant antiangiogenic and pro-apoptotic effects in this setting, longer periods of exposure than the ones supported by our heterologous model and/or assays in homologous mouse models of endometriosis may be necessary to detect an effect of this compound on lesion size.

Keywords: Endometriosis; angiogenesis; apoptosis; mouse model; pIC(PEI).